Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1999-02-12
2002-07-09
Ketter, James (Department: 1632)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C435S252300, C435S325000, C435S320100
Reexamination Certificate
active
06417342
ABSTRACT:
1. BACKGROUND OF THE INVENTION
Macular degeneration is a clinical term that is used to describe a variety of diseases that are all characterized by a progressive loss of central vision associated with abnormalities of Bruch's membrane and the retinal pigment epithelium. These disorders include very common conditions that affect older patients (age related macular degeneration or AMD) as well as rarer, earlier-onset dystrophies that in some cases can be detected in the first decade of life
1-18
. The genes associated with some of these dystrophies have been mapped,
5-14
and in three cases, blue-cone monochromasy,
15
pattern dystrophy,
16,17
and Sorsby fundus dystrophy,
18
actually identified. However, none of the latter genes has been found to be responsible for a significant fraction of typical late-onset macular degeneration.
In developed countries, AMD is the most common cause of legal blindness in older patients.
19
The hallmark of this condition is the presence of drusen, which are ophthalmoscopically visible, yellow-white hyaline excrescences of Bruch's membrane. In some families, drusen are heritable in an autosomal dominant fashion.
In 1875, Hutchinson and Tay published a paper entitled “Symmetrical Central Choroido-Retinal Disease Occurring in Senile Persons”.
20
This paper includes one of the first descriptions of the constellation of clinical findings now known as age related macular degeneration (AMD). Specifically, three of the ten patients in the report were sisters affected with whitish spots (now referred to as drusen) in the macula. In 1899, Doyne
21
reported a similar disorder in which the abnormal spots were nearly confluent such that the macula had a “honeycomb” appearance. Histopathologic examination of one of Doyne's patients
22
revealed the abnormalities to be hyaline thickenings of Bruch's membrane. In 1925, Vogt
23
published the first description of the ophthalmoscopic appearance of a form of familial drusen that had been observed in patients living in the Leventine valley in the Ticino canton of southern Switzerland. Klainguti
24
fully characterized this condition in 1932 and demonstrated its autosomal dominant inheritance. This disorder eventually became known as malattia leventinese (i.e., Leventine disease). In 1948, Waardenburg
25
stated that there was little reason to make a distinction between malattia leventinese and the condition described by Doyne. This position was strengthened when Forni and Babel
26
found that the histopathologic features of malattia leventinese were indistinguishable from those of Doyne's honeycomb choroiditis. Piguet, Haimovici and Bird
27
recently reviewed the history of these conditions and also pointed out that the drusen in families with malattia leventinese are frequently distributed in a radical pattern (see also FIGS.
2
and
3
). Choroidal neovascularization is uncommon in patients with radial drusen but does occur.
27
Although originally recognized in Switzerland, families affected with autosomal dominant radial drusen have been identified in Czechoslovakia,
28,29
and the United States.
30
Currently, there is no therapy that is capable of significantly slowing the degenerative progression of AMD, and treatment is limited to laser photocoagulation of the subretinal neovascular membranes that occur in 10-15% of affected patients.
2. SUMMARY OF THE INVENTION
In one aspect the invention features methods for diagnosing a subject with macular degeneration or with a predisposition for developing macular degeneration. In a preferred embodiment, the diagnostic methods utilize a set of primers and/or probes for amplifying and/or detecting regions of the macular degeneration causing gene, and means for analyzing the macular degeneration causing gene for differences (mutations) from the normal coding sequence. For example, the MD causative mutation can be detected by any of a variety of available techniques, including: 1) performing a hybridization reaction between a nucleic acid sample and a probe that is capable of hybridizing to the allele; 2) sequencing at least a portion of the allele; or 3) determining the electrophoretic mobility of the allele or fragments thereof (e.g., fragments generated by endonuclease digestion). The allele can optionally be subjected to an amplification step prior to performance of the detection step. Preferred amplification methods are selected from the group consisting of: the polymerase chain reaction (PCR), the ligase chain reaction (LCR), strand displacement amplification (SDA), cloning, and variations of the above (e.g. RT-PCR and allele specific amplification). Oligonucleotides necessary for amplification may be selected from anywhere in the IL-1 gene loci, either flanking the marker of interest (as required for PCR amplification) or directly overlapping the marker (as in ASO hybridization). The DNA in the human IL-1 region has been mapped, and oligonucleotides for primers can easily be selected with a commercially available primer selection program. In a particularly preferred embodiment, the sample is hybridized with a set of primers, which hybridize 5′ and 3′ in a sense or antisense sequence to the mutation, and is subjected to a PCR amplification. In a preferred embodiment, the MD causative mutation results in the following amino acid substitutions to the FBNL protein: 345Arg>Trp and 362 Arg>Gln.
In another embodiment, the diagnostic methods employ antibodies to a macular degeneration causing protein (i.e. a protein encoded by the macular degeneration gene) in an immunoassay procedure to detect the presence of a macular degeneration causing protein in a subject's bodily fluid (e.g. tears).
In another aspect, the invention features kits for performing the above-described assays. The kit can include sample collection means and a means for determining whether a subject carries an MD causative mutation. The kit may also comprise control samples, either negative or positive, or standards.
Information obtained using the assays and kits described herein is useful, for example, for identifying presymptomatic individuals, who are at risk for developing MD, e.g. based on family history. If the diagnosis is negative, the individual will not need to worry about the potential development of the disease over time. If the diagnosis is positive, steps may be taken to prevent or ameliorate the effects of the disease before damage, such as loss of vision, occurs. In addition, the information can allow a more customized approach to prolonging the onset or treating the symptoms associated with MD. For example, this information can enable a doctor to: 1) more effectively prescribe a drug that will address the molecular basis of MD in the subject; and/or 2) better determine the appropriate drug and dosage of a particular drug for the particular subject.
In yet a further aspect, the invention features methods for treating or preventing the development of MD in a subject by administering to the subject, a pharmaceutically effective amount of an MD therapeutic of the invention. In one embodiment, the MD therapeutic is a macular degeneration correcting gene or protein (i.e. a “normal” FBNL or related gene or protein (e.g. fibulin 1 or fibulin 2), which corresponds to a mutated gene or defective protein that causes the development of macular degeneration). In another embodiment, the MD therapeutic is an antagonist of the mutant protein activity or an agonist of the wildtype protein activity.
The instant disclosed MD therapeutics correct the biochemical defect resulting in disease. Therefore the instant disclosed therapies offer a major advance over current treatments (e.g. laser photocoagulation of the subretinal neovascular membranes that only occur in 10-15% of affected patients.
In still another aspect, the invention provides in vitro and in vivo assays for screening test compounds to identify MD therapeutics. In another embodiment, the invention features transgenic non-human animals and their use, for example in identifying MD therapeutics.
O
Sheffield Val C.
Stone Edwin M.
Ketter James
Needle & Rosenberg P.C.
Schnizer Richard
University of Iowa Research Foundation
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